Medicine Matters rheumatology

So the SPIRIT-P3 study which I'm presenting here in ACR is a very novel trial design, and it's looking at withdrawing drug in patients who have done well. And it's one of the first large-scale withdrawal studies that we've seen specifically in PsA. So these were patients who were treated with ixekizumab. It was open-label. They knew that they were getting the drug. And then, if they reached MDA, the minimal disease activity criteria consistently for three months-- so on four separate occasions each four weeks apart.

Then they were randomized either to continue on the drug or to switch to placebo. So they then didn't know what they were receiving. They were randomized from that point onwards. So they'd been on the drug potentially up to nine months. So obviously people achieved MDA at different times after starting the drug. But then they had it withdrawn. And what we saw is a very high relapse rate in patients who were withdrawn to placebo.

We saw some relapses in the patients who actually continued on the drug. So there are two possible explanations for that. One is that, obviously, psychologically they were concerned that their drug had been withdrawn-- that might have affected some of their patient reported outcomes. And also there may have been just a bit of natural variation in their states. So if they had just achieved MDA and then maybe lost control in one domain, then that would have counted as a flare.

And then the follow-up part to the study was obviously to give the drug back to people who had struggled. So as soon as people reported a flare and lost their MDA state. Then they were eligible to go back onto ixekizumab-- and nearly all of them recaptured very quickly. So we know that stopping the drug completely is very risky, that we're going to see a high rate of flare-- up to 90% for patients who were left longer. But if we then get them back on drug, they stand a good chance of recapturing that same disease control.

I think that this is helpful in taking us forward because this kind of study has never been done. It's a very different picture from axial spondyloarthritis. So in axSpA, we see that some patients can withdraw the drug and actually stay well-- but in PsA, they really can't. These patients who admittedly have more severe disease-- they're at the severer end of the spectrum for the patients that we see, but you see a very high relapse rate.

So I think it would put us off doing future studies like this, where we stopped the drug completely. I think where we need to focus our efforts now is on tapering. So we may not be able to stop the drug completely. But we've got a number of smaller observational studies which suggest we can probably taper the dose in patients doing very well. And then we can minimize any risks from the drug, save the costs, and keep people well.

Through the additional analysis that we did on the same study, we're looking at which components of MDA actually caused the flare. So when we're thinking about patients in MDA, there are seven different domains. So there's tender joints, swollen joints, enthesitis, skin pain, global, and HAQ. And any of those components losing control could cause a loss of the MDA criteria overall. And so we looked at which components tended to be associated with the flare. And actually we saw a difference between drug and placebo for all of the components-- except for HAQ and enthesitis.

So I think the HAQ makes sense. We're not seeing such a quick change in somebody's functional status. That tends to be a slower change. But we did see some patients who flared with tenderness, some patients flaring with swelling, some patients whose skin flared, and some patients showing increase in pain and global scores. So it was really different disease activity across the board, when you're comparing those who continued on the ixekizumab, with those who had it withdrawn and switched to placebo.